Downregulation of lncRNA CCHE1 inhibits cell proliferation, migration and invasion by suppressing MEK/ERK/c-MYC pathway in nasopharyngeal carcinoma.

OBJECTIVE: The current study was designed to investigate the functionality of lncRNA CCHE1 in nasopharyngeal carcinoma. MATERIALS AND METHODS: MiRNA levels of lncRNA CCHE1 were examined by RT-qPCR. CCK8 assay and colony formation assay were together performed to detect cell proliferation viability. Furthermore, wound healing assay and transwell assay were respectively conducted to assess cell migration and invasion. In addition, proteins related to MEK/ERK/c-MYC pathway were detected by Western blot. RESULTS: Elevated levels of CCHE1 were verified in NPC cell lines. Downregulation of CCHE1 significantly inhibited tumor growth and suppressed A549 cell proliferation, migration and invasion. MEK/ERK/c-MYC pathway was activated in nasopharyngeal carcinoma. Treatment of PD98059 (MEK inhibitor) or SCH772984 (ERK inhibitor) reversed the effects of CCHE1 on cell proliferation, migration and invasion in NPC. CONCLUSIONS: The present study suggested that downregulation of lncRNA CCHE1 could inhibit cell proliferation, migration and invasion by suppressing MEK/ERK/c-MYC pathway in nasopharyngeal carcinoma.

Profiling of how nociceptor neurons detect danger - new and old foes.

The host evolves redundant mechanisms to preserve physiological processing and homeostasis. These functions range from sensing internal and external threats, creating a memory of the insult and generating reflexes, which aim to resolve inflammation. Impairment in such functioning leads to chronic inflammatory diseases. By interacting through a common language of ligands and receptors, the immune and sensory nervous systems work in concert to accomplish such protective functions. Whilst this bidirectional communication helps to protect from danger, it can contribute to disease pathophysiology. Thus, the somatosensory nervous system is anatomically positioned within primary and secondary lymphoid tissues and mucosa to modulate immunity directly. Upstream of this interplay, neurons detect danger, which prompts the release of neuropeptides initiating (i) defensive reflexes (ranging from withdrawal response to coughing) and (ii) chemotaxis, adhesion and local infiltration of immune cells. The resulting outcome of such neuro-immune interplay is still ill-defined, but consensual findings start to emerge and support neuropeptides not only as blockers of TH 1-mediated immunity but also as drivers of TH 2 immune responses. However, the modalities detected by nociceptors revealed broader than mechanical pressure and temperature sensing and include signals as various as cytokines and pathogens to immunoglobulins and even microRNAs. Along these lines, we aggregated various dorsal root ganglion sensory neuron expression profiling datasets supporting such wide-ranging sensing capabilities to help identifying new danger detection modalities of these cells. Thus, revealing unexpected aspects of nociceptor neuron biology might prompt the identification of novel drivers of immunity, means to resolve inflammation and strategies to safeguard homeostasis.

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Genome-wide association study identifies a novel locus for cannabis dependence.

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

Valproic acid attenuates the risk of acute respiratory failure in patients with subarachnoid hemorrhage.

BACKGROUND: Valproic acid (VPA) has shown potent anti-inflammatory effect and attenuates acute lung injury. AIM: To determine whether the use of VPA is associated with a decreased risk of acute respiratory failure (ARF) in patients with subarachnoid hemorrhage (SAH). DESIGN: The Taiwan National Health Insurance Research Database was used to analyse all patients newly diagnosed with SAH from 2000 to 2010. The VPA users were matched for age, gender and index date in 1:2 ratios with randomly selected non-VPA users as a comparison group. METHODS: Multivariate Cox regression was used to identify the predictors of ARF and to compare the incidence rates of ARF among SAH patients using and not using VPA. RESULTS: The study cohort included 16 228 newly diagnosed SAH patients, from which 521 VPA users and 1042 matched non-VPA-exposed individuals were selected. In the VPA-treated cohort and the non-VPA-treated cohort, 117 and 289 patients developed ARF, respectively. Any use of VPA was associated with a 16% decreased risk of ARF requiring mechanical ventilation in 30-day tracking of the SAH patients (adjusted hazard ratio [HR], 0.840, 95% confidence interval [CI], 0.676-0.945). Age, sepsis and pneumonia were identified as independent predictors of ARF in patients with SAH. After stratification, VPA users showed a lower risk of ARF among SAH patients complicated with pneumonia compared with non-users of VPA (adjusted HR, 0.816, 95% CI, 0.652-0.921). CONCLUSIONS: Any use of VPA was associated with a reduced risk of ARF in patients with SAH. VPA may be beneficial for decreasing the risk of pneumonia-induced ARF in patients with SAH.

Age-, sex- and glucose-dependent correlation of plasma soluble vascular adhesion protein-1 concentration with cardiovascular risk factors and subclinical atherosclerosis.

OBJECTIVE: Soluble vascular adhesion protein-1 (sVAP-1) may act as a biomarker for atherosclerosis and cardiovascular diseases. The associations of sVAP-1 concentration with cardiovascular risk factors and subclinical atherosclerosis at the population level have not been reported. PATIENTS AND METHODS: This cross-sectional study included 834 asymptomatic subjects (49.1 ± 9.3 years). sVAP-1 was measured by enzyme-linked immunosorbent assay. Subclinical atherosclerosis was assessed by brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (CIMT). RESULTS: sVAP-1 increased with age. Women had a higher concentration than men in age > 40 years. In women, sVAP-1 was negatively associated with estradiol (p < 0.01) and body mass index (BMI) (p < 0.05). In men, sVAP-1 was negatively associated with apolipoprotein A (ApoA) (p < 0.01), alcohol intake (p < 0.01) and uric acid (p < 0.05), but positively associated with ApoB/ApoA (p < 0.05). In hyperglycemia subjects, sVAP-1 positively correlated with fasting plasma glucose (p < 0.05) and hemoglobin A1c (p < 0.05), but in normoglycemic subjects, sVAP-1 negatively correlated with BMI (p < 0.01), triglyceride (p < 0.05), alcohol intake (p < 0.05). sVAP-1 independently influenced CIMT (ß = 0.001, p = 0.040) and carotid plaques [odds ratio 1.380 (95% confidence interval 1.051-1.813, p = 0.021)] in hyperglycemia, and baPWV (ß = 31.605, p = 0.014) in age > 55 years. CONCLUSIONS: sVAP-1 concentration correlates with cardiovascular risk factors and subclinical atherosclerosis in an age-, sex- and glucose-dependent manner.

Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

Mongolian Almond (Prunus mongolica Maxim): The Morpho-Physiological, Biochemical and Transcriptomic Response to Drought Stress.

Prunus mongolica Maxim, which is widely established in the Gobi Desert, shows extreme tolerance to drought. However, there is a lack of available transcriptomic resources for this species related to its response to water deficiency. To investigate the mechanisms that allow P. mongolica to maintain growth in extremely arid environments, the response of P. mongolica seedlings to drought stress was analyzed using morphological, physiological, biochemical and high-throughput sequencing approaches. We generated 28,713,735 and 26,650,133 raw reads from no-stress control and drought-stressed P. mongolica seedlings, respectively. In total, we obtained 67,352 transcripts with an average length of 874.44 bp. Compared with the no-stress control, 3,365 transcripts were differentially expressed in the drought-stressed seedlings, including 55.75% (1,876 transcripts) up-regulated and 44.25% (1,489 transcripts) down-regulated transcripts. The photosynthesis response showed a decreasing tendency under drought stress, but the changes in the levels of hormones (auxins, cytokinins and abscisic acid) resulted in the closing of stomata and decreased cell enlargement and division; these changes were effective for promoting P. mongolica survival in Gobi Desert. Next, we analyzed the aquaporin and superoxide dismutase gene families due to their importance in plant resistance to drought stress. We found that all of the plasma membrane intrinsic protein transcripts were down-regulated in the drought-stressed treatment, whereas drought did not affect the expression of nodulin intrinsic protein or small basic intrinsic protein transcripts in P. mongolica seedlings. In addition, activation of iron superoxide dismutase transcription and enhanced transcription of manganese superoxide dismutase were observed in P. mongolica to promote tolerance of drought stress. This study identified drought response genes in P. mongolica seedlings. Our results provide a significant contribution to the understanding of how P. mongolica responds to drought stress at the transcriptome level, which may help to elucidate molecular mechanisms associated with the drought response of almond plants.

MK-571 attenuates kidney ischemia and reperfusion-induced airway hypersensitivity in rats.

OBJECTIVE: Reperfusion of the rat kidney has been shown to up-regulate cysteinyl leukotriene-1 receptor, an asthma-associated gene in human bronchioles, and increase expression of leukotriene D4. In this study, we aimed to investigate the efficacy of MK-571, a leukotriene D4 inhibitor, against hypersensitivity induced by kidney ischemia and reperfusion (I/R)-associated acute kidney injury. METHODS: Sprague-Dawley male rats were divided into 3 study groups: a sham-operated group, a kidney I/R group, and a group treated with MK-571 before the kidney I/R injury: MK-571 (5 mg/kg) was administered intraperitoneally 15 minutes before ischemia and every 12 hours after reperfusion up to 24 hours. Ischemia was conducted by bilateral occlusion of renal pedicles for 45 minutes, followed by releasing the clamps and closing the abdominal incision. Respiratory function was tested 24 hours after reperfusion, with the use of a 2-chamber whole body plethysmograph for conscious rats. Blood samples, pulmonary bronchoalveolar lavage fluid, and lung tissues were collected at the end of study. In 10 rats, urine was collected at baseline and the end of study. RESULTS: Compared with the sham group, kidney I/R injury markedly increased enhanced pause (Penh) index during methacholine challenge test (P < .05), suggesting airway hypersensitivity; it also increased in inflammatory response and levels of hydroxyl radical production and lipid peroxidation in the lungs. In contrast, in MK-571-treated rats, Penh was muted during methacholine challenge test (P < .05). CONCLUSIONS: Kidney I/R injury induces airway hypersensitivity to methacholine challenge test and inflammatory response and oxidative stress in the lungs. Treatment with MK-571, a leukotriene D4 inhibitor, effectively attenuates airway hypersensitivity, pulmonary inflammatory response, and lung and kidney injury.

Orally active microtubule-targeting agent, MPT0B271, for the treatment of human non-small cell lung cancer, alone and in combination with erlotinib.

Microtubule-binding agents, such as taxanes and vinca alkaloids, are used in the treatment of cancer. The limitations of these treatments, such as resistance to therapy and the need for intravenous administration, have encouraged the development of new agents. MPT0B271 (N-[1-(4-Methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-1-oxy-isonicotinamide), an orally active microtubule-targeting agent, is a completely synthetic compound that possesses potent anticancer effects in vitro and in vivo. Tubulin polymerization assay and immunofluorescence experiment showed that MPT0B271 caused depolymerization of tubulin at both molecular and cellular levels. MPT0B271 reduced cell growth and viability at nanomolar concentrations in numerous cancer cell lines, including a multidrug-resistant cancer cell line NCI/ADR-RES. Further studies indicated that MPT0B271 is not a substrate of P-glycoprotein (P-gp), as determined by flow cytometric analysis of rhodamine-123 (Rh-123) dye efflux and the calcein acetoxymethyl ester (calcein AM) assay. MPT0B271 also caused G2/M cell-cycle arrest, accompanied by the up-regulation of cyclin B1, p-Thr161 Cdc2/p34, serine/threonine kinases polo-like kinase 1, aurora kinase A and B and the downregulation of Cdc25C and p-Tyr15 Cdc2/p34 protein levels. The appearance of MPM2 and the nuclear translocation of cyclin B1 denoted M phase arrest in MPT0B271-treated cells. Moreover, MPT0B271 induced cell apoptosis in a concentration-dependent manner; it also reduced the expression of Bcl-2, Bcl-xL, and Mcl-1 and increased the cleavage of caspase-3 and -7 and poly (ADP-ribose) polymerase (PARP). Finally, this study demonstrated that MPT0B271 in combination with erlotinib significantly inhibits the growth of the human non-small cell lung cancer A549 cells as compared with erlotinib treatment alone, both in vitro and in vivo. These findings identify MPT0B271 as a promising new tubulin-binding compound for the treatment of various cancers.

Curcumin attenuates renal ischemia and reperfusion injury-induced restrictive respiratory insufficiency.

OBJECTIVE: Pulmonary failure, instead of kidney failure, is one of the leading causes of acute kidney injury (AKI)-related death. Volume overload was previously regarded as the primary cause of lung injury, presumably by impaired renal fluid clearance. Recent evidence suggested that proinflammatory cytokines, chemokines, and free radicals released during AKI are playing a crucial role in the lung injury. We aimed to examine the protective efficacy of lung function with curcumin pretreatment. METHODS: AKI was induced by 45 minutes of kidney ischemia (bilateral occlusion of renal pedicles) followed by 3 hours of reperfusion. Rats were divided into 3 groups: sham-operated, kidney ischemia and reperfusion (I/R), and a group with 2 days of oral pretreatment with curcumin (12.5 mg/kg/d) before I/R injury. The pulmonary function test (PFT) was conducted at baseline and after 3 hours of reperfusion, yielding parameters of lung volumes, chord compliance (Cchord), inspiratory resistance (RI), and forced expiratory volume at the first 200 millisecond (FEV200). We also examined levels of protein concentration (PC), methylguanidine (MG), tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA) in the bronchoalveolar lavage (BAL). RESULTS: Ischemic AKI-induced restrictive lung disease was demonstrated by the decreased Cchord, total lung capacitance (TLC), and FEV200, in addition to the increased lavage PCBAL, MG, TNF-α, and MDA level. Curcumin pretreatment ameliorated lung function impairment and alveolar vascular protein leak and attenuated lung inflammation. CONCLUSIONS: The protective effect of curcumin pretreatment against restrictive lung disease is most likely associated with decreasing hydroxyl radical, lipid peroxidation, and inflammation in the lungs and improving alveolar vascular permeability.

Curcumin treatment protects against renal ischemia and reperfusion injury-induced cardiac dysfunction and myocardial injury.

OBJECTIVES: Renal ischemia and reperfusion (I/R) injury frequently leads to acute renal failure (ARF) and multiple-organ injury with a substantial morbidity rate. The primary cause of ARF-associated death is, however, cardiac failure instead of renal failure itself, and the pathogenesis of renal I/R-induced cardiac injury is still poorly understood. We evaluated the efficacy of curcumin pretreatment on cardioprotection. METHODS: Thirty Sprague-Dawley rats were evenly divided into 3 groups of sham-operated control, renal I/R injury, and a curcumin pretreatment group. Renal ischemia was conducted by bilateral occlusions of pedicles for 45 minutes, followed by 3 hours of reperfusion. The cardiac function was assessed by the left ventricular end-systolic-pressure-volume-relation (ESPVR), systolic pressure (SP), ejection fraction (EF), and stroke volume (SV). Myocardial injury was assessed based on creatine kinase muscle brain fraction (CK-MB) and Troponin I (cTnI), and kidney injury was assessed based on blood urea nitrogen (BUN) and creatinine. We also assessed the levels of tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) in the heart tissues. RESULTS: SV, EF, and SP reduced moderately during the ischemic phase with no major change in ESPVR. During reperfusion, SV, SP, and ESPVR initially increased, and then steadily decreased. Myocardial and kidney injury were marked by the increases in serum CK-MB and cTnI, and creatinine and BUN level. Curcumin pretreatment ameliorated ESPVR and attenuated injuries of both the heart and kidney resulting from I/R insult. CONCLUSIONS: Curcumin pretreatment improved cardiac contractility and attenuated myocardial and renal injury through reducing inflammatory response in the kidney and heart and oxidative stress in the myocardium.

N-acetylcysteine improves cardiac contractility and ameliorates myocardial injury in a rat model of lung ischemia and reperfusion injury.

OBJECTIVES: Lung ischemia and reperfusion (I/R) injury is the major complication subsequent to cardiopulmonary bypass surgery and lung transplantation. Lung I/R injury frequently induces cardiac dysfunction leading to significant mortality. So far, the literature on therapeutic interventions in cardiac dysfunction and myocardial injury is still scarce. In this study, we examined the efficacy of N-acetylcysteine (NAC) administration against lung I/R injury-induced cardiac dysfunction. METHODS: Lung ischemia was established by occluding the left lung hilum for 60 minutes, followed by 2 hours of reperfusion. Studies were performed in 3 groups: sham-operated (same surgical procedure except vessel occlusion; N = 8), lung I/R injury (N = 12), and NAC-administered group (N = 12). The cardiac function was assessed using simultaneous left ventricular (LV) pressure and volume measured via a high-fidelity pressure-volume catheter. Myocardial injury was assessed based on serum creatine kinase muscle brain fraction (CK-MB) and troponin I (cTnI) level, and lung injury based on the degree of protein concentration in lung lavage. We also examined the degrees of myocardial lipid peroxidation and hydroxyl radical production with and without NAC. RESULTS: During lung ischemia, LV stiffness increased with relative intact contractility. After 2 hours of reperfusion, LV contractility decreased with dilated and stiffened ventricle, along with apparent myocardial and lung injury. NAC administration effectively attenuated heart and lung injury, and ameliorated impaired LV contractility and stiffening resulting from lung I/R injury. CONCLUSIONS: NAC administration reduced lung I/R-induced increases in myocardial hydroxyl radical production and lipid peroxidation, and ameliorated LV contractility and stiffening.

The HDAC inhibitor, MPT0E028, enhances erlotinib-induced cell death in EGFR-TKI-resistant NSCLC cells.

Epidermal growth factor receptor (EGFR), which promotes cell survival and division, is found at abnormally high levels on the surface of many cancer cell types, including many cases of non-small cell lung cancer. Erlotinib (Tarceva), an oral small-molecule tyrosine kinase inhibitor, is a so-called targeted drug that inhibits the tyrosine kinase domain of EGFR, and thus targets cancer cells with some specificity while doing less damage to normal cells. However, erlotinib resistance can occur, reducing the efficacy of this treatment. To develop more effective therapeutic interventions by overcoming this resistance problem, we combined the histone deacetylase inhibitor, MPT0E028, with erlotinib in an effort to increase their antitumor effects in erlotinib-resistant lung adenocarcinoma cells. This combined treatment yielded significant growth inhibition, induced the expression of apoptotic proteins (PARP, γH2AX, and caspase-3), increased the levels of acetylated histone H3, and showed synergistic effects in vitro and in vivo. These effects were independent of the mutation status of the genes encoding EGFR or K-Ras. MPT0E028 synergistically blocked key regulators of the EGFR/HER2 signaling pathways, attenuating multiple compensatory pathways (e.g., AKT, extracellular signal-regulated kinase, and c-MET). Our results indicate that this combination therapy might be a promising strategy for facilitating the effects of erlotinib monotherapy by activating various networks. Taken together, our data provide compelling evidence that MPT0E028 has the potential to improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents.

A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.

Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.

Active drug targeting of disease by nanoparticles functionalized with ligand to folate receptor.

Drug-loaded nanoparticles have shown great potential in the study of carriers for disease-targeting drug delivery. Drug-loaded nanoparticles are excellent in keeping the drug in the systemic circulation for a prolonged period of time, introducing targeting molecules to improve targeting efficiency and to reduce side effects. A general review on active drug targeting of cancerous diseases by nanoparticles functionalized with ligands to folate receptors is presented including the (1) materials and methods for nanoparticle preparation, (2) methods for drug encapsulation, (3) surface functionalization of the nanoparticle with ligand to folate receptors, and (4) in vitro and in vivo experiments.

Family-based genome-wide association study of frontal θ oscillations identifies potassium channel gene KCNJ6.

Event-related oscillations (EROs) represent highly heritable neuroelectric correlates of cognitive processes that manifest deficits in alcoholics and in offspring at high risk to develop alcoholism. Theta ERO to targets in the visual oddball task has been shown to be an endophenotype for alcoholism. A family-based genome-wide association study was performed for the frontal theta ERO phenotype using 634 583 autosomal single nucleotide polymorphisms (SNPs) genotyped in 1560 family members from 117 families densely affected by alcohol use disorders, recruited in the Collaborative Study on the Genetics of Alcoholism. Genome-wide significant association was found with several SNPs on chromosome 21 in KCNJ6 (a potassium inward rectifier channel; KIR3.2/GIRK2), with the most significant SNP at P = 4.7 × 10(-10)). The same SNPs were also associated with EROs from central and parietal electrodes, but with less significance, suggesting that the association is frontally focused. One imputed synonymous SNP in exon four, highly correlated with our top three SNPs, was significantly associated with the frontal theta ERO phenotype. These results suggest KCNJ6 or its product GIRK2 account for some of the variations in frontal theta band oscillations. GIRK2 receptor activation contributes to slow inhibitory postsynaptic potentials that modulate neuronal excitability, and therefore influence neuronal networks.

Ataxic sensory neuronopathy in a patient with systemic lupus erythematosus.

The occurrence of ataxic sensory neuronopathy (ASN) is rare in patients with connective tissue diseases (CTDs). ASN has been described in case reports and case series in patients with CTDs, mostly Sjögren's syndrome, and most often occurring during middle or old age. ASN in association with systemic lupus erythematosus (SLE) is extremely rare; there has been only one reported case in the literature. In addition, to our knowledge, adolescent onset of symptoms in CTD-associated ASN has not been reported previously. We report the case of a young woman who presented with ASN, characterized by sensory ataxia, with elevated antinuclear antibodies, leukopenia and anemia; she fulfilled the diagnostic criteria for SLE about 7 years after the onset of sensory ataxia. Our case points out that ASN may be the initial presenting feature of SLE. SLE should be included in the differential diagnosis of ASN, especially in patients of young age.

CCMG guidelines: prenatal and postnatal diagnostic testing for uniparental disomy.

The aim of this statement is to provide clinicians, cytogeneticists and molecular geneticists of the Canadian College of Medical Geneticists (CCMG) a comprehensive review of the role of UPD in constitutional genetic diagnosis and to provide a guideline as to when investigation for UPD is recommended. Members of the CCMG Cytogenetics, Molecular Genetics, Clinical Practice, and Prenatal Diagnosis committees reviewed the relevant literature on uniparental disomy (UPD) in constitutional genetic diagnosis (May 2010). Guidelines were developed for UPD testing in Canada. The guidelines were circulated for comment to the CCMG members at large and following appropriate modification, approved by the CCMG Board of Directors (July 2010).